Zevalin (Ibritumomab Tiuxetan) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Safety data, except where indicated, are based upon 349 patients treated in 5 clinical studies with the ZEVALIN therapeutic regimen (see DOSAGE AND ADMINISTRATION). Because the ZEVALIN therapeutic regimen includes the use of Rituximab, also see prescribing information for RITUXAN (Rituximab).

The most serious adverse reactions caused by the ZEVALIN therapeutic regimen include infections (predominantly bacterial in origin), allergic reactions (bronchospasm and angioedema), and hemorrhage while thrombocytopenic (resulting in deaths). In addition, patients who have received the ZEVALIN therapeutic regimen have developed myeloid malignancies and dysplasias. Fatal infusion reactions have occurred following the infusion of Rituximab. Please refer to the BOX WARNINGS and WARNINGS sections for detailed descriptions of these reactions.

The most common toxicities reported were neutropenia, thrombocytopenia, anemia, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea), increased cough, dyspnea, dizziness, arthralgia, anorexia, anxiety, and ecchymosis. Hematologic toxicity was often severe and prolonged, whereas most non-hematologic toxicity was mild in severity. Table 7 lists adverse events that occurred in >/= 5% of patients. A more detailed description of the incidence and duration of hematologic toxicities, according to baseline platelet count (as an indicator of bone marrow reserve) is provided in Table 8, Hematologic Toxicity.

The following adverse events (except for those noted in Table 7) occurred in between 1 and 4% of patients during the treatment period: urticaria (4%), anxiety (4%), dyspepsia (4%), sweats (4%), petechia (3%), epistaxis (3%), allergic reaction (2%), and melena (2%).

Severe or life-threatening adverse events occurring in 1-5% of patients (except for those noted in Table 7) consisted of pancytopenia (2%), allergic reaction (1%), gastrointestinal hemorrhage (1%), melena (1%), tumor pain (1%), and apnea (1%). The following severe or life threatening events occurred in <1% of patients: angioedema, tachycardia, urticaria, arthritis, lung edema, pulmonary embolus, encephalopathy, hematemesis, subdural hematoma, and vaginal hemorrhage.

Hematologic Events: Hematologic toxicity was the most frequently observed adverse event in clinical trials. Table 8 presents the incidence and duration of severe hematologic toxicity for patients with normal baseline platelet count (>/= 150,000 cells/mm³) treated with the ZEVALIN therapeutic regimen and patients with mild thrombocytopenia (platelet count 100,000 to 149,000 cells/mm³) at baseline who were treated with a modified ZEVALIN therapeutic regimen that included a lower Y-90 ZEVALIN dose at 0.3 mCi/kg (11.1 MBq/kg).

Median time to ANC nadir was 62 days, to platelet nadir was 53 days, and to hemoglobin nadir was 68 days. Information on growth factor use and platelet transfusions is based on 211 patients for whom data were collected. Filgrastim was given to 13% of patients and erythropoietin to 8%. Platelet transfusions were given to 22% of patients and red blood cell transfusions to 20%.

Infectious Events: During the first 3 months after initiating the ZEVALIN therapeutic regimen, 29% of patients developed infections. Three percent of patients developed serious infections comprising urinary tract infection, febrile neutropenia, sepsis, pneumonia, cellulitis, colitis, diarrhea, osteomyelitis, and upper respiratory tract infection. Life threatening infections were reported for 2% of patients that included sepsis, empyema, pneumonia, febrile neutropenia, fever, and biliary stent-associated cholangitis. During follow-up from 3 months to 4 years after the start of treatment with ZEVALIN, 6% of patients developed infections. Two percent of patients had serious infections comprising urinary tract infection, bacterial or viral pneumonia, febrile neutropenia, perihilar infiltrate, pericarditis, and intravenous drug-associated viral hepatitis. One percent of patients had life threatening infections that included bacterial pneumonia, respiratory disease, and sepsis.

Secondary Malignancies: A total of 2% of patients developed secondary malignancies following the ZEVALIN therapeutic regimen. One patient developed a Grade 1 meningioma, three developed acute myelogenous leukemia, and two developed a myelodysplastic syndrome. The onset of a second cancer was 8-34 months following the ZEVALIN therapeutic regimen and 4 to 14 years following the patients' diagnosis of NHL.

Immunogenicity: Of 211 patients who received the ZEVALIN therapeutic regimen in clinical trials and who were followed for 90 days, there were eight (3.8%) patients with evidence of human anti-mouse antibody (HAMA) (n=5) or human anti-chimeric antibody (HACA) (n=4) at any time during the course of the study. Two patients had low titers of HAMA prior to initiation of the ZEVALIN therapeutic regimen; one remained positive without an increase in titer while the other had a negative titer post-treatment. Three patients had evidence of HACA responses prior to initiation of the ZEVALIN therapeutic regimen; one had a marked increase in HACA titer while the other two had negative titers post-treatment. Of the three patients who had negative HAMA or HACA titers prior to the ZEVALIN therapeutic regimen, two developed HAMA in absence of HACA titers, and one had both HAMA and HACA positive titers post-treatment. Evidence of immunogenicity may be masked in patients who are lymphopenic. There has not been adequate evaluation of HAMA and HACA at delayed timepoints, concurrent with the recovery from lymphopenia at 6-12 months, to establish whether masking of the immunogenicity at early timepoints occurs. The data reflect the percentage of patients whose test results were considered positive for antibodies to Ibritumomab or Rituximab using kinetic enzyme immunoassays to Ibritumomab and Rituximab. The observed incidence of antibody positivity in an assay is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including sample handling and concomitant medications. Comparisons of the incidence of HAMA/HACA to the ZEVALIN therapeutic regimen with the incidence of antibodies to other products may be misleading.